Plasmodium falciparum causes fatal malaria in over 2 million children a year in endemic areas. Resistance to chloroquine, the drug of choice for treatment, is widespread. We have developed a series of aminoquinolines (AQ) by modification of the diaminoalkane side chain of chloroquine, that are active in vitro against chloroquine-resistant P. falciparum. We tested one of the most promising long-chain compounds in rhesus macaques infected with P. cynomolgi, a monkey malaria parasite. Because of the excellent efficacy in vitro, we were surprised when the compound was not active against parasites in the monkey. We suspect that the drug is metabolized by the cytochrome P450 system in the liver and we are now isolating the metabolites of this drug using an in vitro system with rhesus monkey microsomes. These metabolites will be tested in vitro for activity against P. falciparum to dissect out the reason for treatment failure in the monkey. Although the evident drug failure is disappointing, it underscores the importance of screening for toxicity and efficacy in a primate model of human malaria before